Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials

  • J Med Chem. 2016 Feb 25;59(4):1330-9. doi: 10.1021/acs.jmedchem.5b01882.
Brian K Albrecht  1 ,  Victor S Gehling  1 ,  Michael C Hewitt  1 ,  Rishi G Vaswani  1 ,  Alexandre Côté  1 ,  Yves Leblanc  1 ,  Christopher G Nasveschuk  1 ,  Steve Bellon  1 ,  Louise Bergeron  1 ,  Robert Campbell  1 ,  Nico Cantone  1 ,  Michael R Cooper  1 ,  Richard T Cummings  1 ,  Hariharan Jayaram  1 ,  Shivangi Joshi  1 ,  Jennifer A Mertz  1 ,  Adrianne Neiss  1 ,  Emmanuel Normant  1 ,  Michael O'Meara  1 ,  Eneida Pardo  1 ,  Florence Poy  1 ,  Peter Sandy  1 ,  Jeffrey Supko  1 ,  Robert J Sims 3rd  1 ,  Jean-Christophe Harmange  1 ,  Alexander M Taylor  1 ,  James E Audia  1
Affiliations
  • 1. Constellation Pharmaceuticals , 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
PMID: 26815195 DOI: 10.1021/acs.jmedchem.5b01882
Abstract

In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, Bcl-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).

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